Salk Chemical Evolution Scientist Leslie Orgel Dies

October 30, 2007

La Jolla, CA – Salk scientist Leslie Orgel, Ph.D., who dedicated much of his career to the study of how life began on Earth roughly 4 billion years ago, died on October 27 from pancreatic cancer. He was 80 years old.

Orgel, a professor and head of the Chemical Evolution Laboratory, aimed not only to discover the chemical reactions that led to the first life forms on the primitive Earth, but also to solve the mystery of how, during this prebiological time, a replicative molecule arose that could pass on life's genetic blueprint to future generations.

He was among the first scientists, in the 1960s, to suggest that RNA, rather than DNA, was that early replicative molecule. He suspected that an even simpler genetic precursor to RNA itself must have existed.

The notion of an "RNA world," as RNA-based life is often called, was coincidentally shared by the scientist who helped discover the structure of DNA – Orgel's Salk colleague and friend, the late Francis Crick.

In acknowledging that common assumptions – such as the belief that DNA is more important than RNA – are often based on lack of evidence, Crick once jokingly credited Orgel with Orgel's Second Rule: "Evolution is cleverer than you are." This statement is now broadly used today as a general rejoinder to arguments made from ignorance.

Born in 1927, in London, England, Leslie Eleazer Orgel earned a bachelor's degree (1949) and his doctorate (1951) in chemistry from Oxford University, and accepted research fellowships at California Institute of Technology and the University of Chicago in 1954 and 1955, respectively. Orgel then returned to Britain and served as assistant director of research at Cambridge's Theoretical Chemistry Department. There he helped develop ligand field theory, which describes chemical bonding in metals. Orgel published An Introduction to Transition-Metal Chemistry: The Ligand Field Theory in 1961.

Orgel became a fellow at the Salk Institute in 1964 and became interested in what distinguishes living organic things from non-living things. He found it intriguing that the proteins found in all of Earth's life forms are made from one set of 20 standard amino acids and that their genetic information is stored in nucleic acids – DNA and RNA – that use the same genetic code. Moreover, RNA uses that information to produce proteins, and proteins, in turn, are needed to help duplicate DNA. But there is a central paradox Orgel and others pointed out: there can be no proteins without DNA, and there can be no DNA without proteins.

Orgel suggested a way out of this chicken-and-egg conundrum, as did Crick and American microbiologist Carol Woese, each of whom published their ideas independently. They speculated that both DNA and proteins could be descendants of RNA. Being more complex and stable, DNA could then have taken over RNA's role as the guardian of heredity, while RNA took on a more supporting role.

Proposing that RNA might have evolved in a way that is consistent with Darwinian selection, Orgel published his thoughts in the 1973 book The Origins of Life: Molecules and Natural Selection.

But more than a decade later, when evidence for an RNA world came with the discovery of an RNA enzymes (ribozymes) that catalyze biochemical reactions, Orgel expressed new doubts. Attempts to form RNA under laboratory conditions that mimic the primordial Earth had been only marginally successful, largely because ribose (a component of the RNA backbone) is a sugar that Orgel said may not have been stable enough to survive the low oxygen and high radiation conditions of the early Earth.

Orgel suggested that RNA probably took over from some more primitive precursor. Accordingly, he and his group at Salk studied alternative genetic backbones that may have preceded nucleic acids. They found that a compound known as peptide nucleic acid (PNA), which is much simpler than RNA, can be copied in the test tube. Their work demonstrated that the evolution of a more complex, self-replicating molecule from a simpler precursor is at least possible.

Orgel's origin-of-life work also had practical applications. During studies in the Chemical Evolution Laboratory, he and his colleagues came across a straightforward way to synthesize cytosine arabinoside (Ara C), a compound that is one of today's most commonly used anti-cancer agents.

Orgel also enjoyed purely theoretical investigations, and mused about how a universal genetic code could have evolved. In 1973, Orgel and Crick put forward the notion that "directed panspermia" – the seeding of life on other worlds by a guiding intelligence – could solve the mystery. In an article in the journal Icarus, they said that while it is possible that life reached Earth in this way, the scientific evidence for this is so inadequate that no one can say anything about the probability. Crick expanded these ideas in his book "Life Itself: Its Origins and Nature."

Because of his long association with NASA, Orgel would have been one of the first to know if other planets had been so seeded. He was one of five principal investigators of the NASA-sponsored research and training program in exobiology. He also participated in NASA's Viking Mars Lander Program as a member of the Molecular Analysis Team that designed the gas chromatography mass spectrometer instrument.

In 1998, he chaired the Task Group on Sample Return from Small Solar Systems Bodies, and served on NASA's astrobiology oversight committee since 1999. Orgel was also part of a strategic planning group for the SETI Institute's Center for the Study of Life in the Universe. In addition to his work at Salk, Orgel was also an adjunct professor in the Department of Chemistry and Biochemistry at UCSD.

Orgel's contributions have been recognized throughout his career. In Britain, he was awarded the Harrison Prize in 1957 for his work in inorganic chemistry, was elected a Fellow of the Royal Society in 1962. In the United States, he received a Guggenheim Fellowship in 1971, the Evans Award from Ohio State University in 1975, and the H.C. Urey Medal from the International Society for the Study of the Origin of Life in 1993. He was elected a member of the National Academy of Sciences in 1990.

Leslie Orgel is survived by his wife, Alice Orgel, M.D., Ph.D., a pediatric allergist, now retired, his two sons Richard and Robert, his daughter Vivienne, and their grandchildren.